The invention concerns a device for the carrying out of investigations on living cells, cell cultures and the like, especially for the detection of metabolic activity of the cells, which find themselves in a liquid medium. The device includes at least a receptor for liquid medium along with the cell culture, and wherein one or more measuring apparatuses and/or sensors for measurement of the cell culture are provided and wherein a movable separation element is provided, which confiningly borders a reaction space.
In the case of such a conventional device, fresh culture medium is admitted to the cells in a specified time sequence, or an active agent dissolved in this culture medium is added. Also, exhausted medium is correspondingly removed from the cell culture zone. A substantial regeneration of the culture medium, for example by means of an appropriate fluid system, produces a far-reaching, constant, physiological milieu. Easily dissociating agents, which are added to the nutrient material, likewise can be regenerated. The added medium and the cell culture zone itself must be protected from contamination by microorganisms and from excessive evaporation. These are important preliminary measures for the sensitive measurement of cellular reactions.
Common to all cell culture operations, is a surface on the bottom for the cell storage and cell growth as well as wall surfaces which form a trough for the containment of the culture medium. The culture medium must be regenerated at regular periods, since the waste products of the cell metabolism accumulate. Nutrient substances are consumed and biological active materials decline in their activity in the course of time.
EP 0 394 406 has already disclosed an apparatus for the fluid handling of cell cultures in combination with sensors. The apparatus of this disclosure possesses a tightly sealed, small volume perfusion chamber, in which the cells are cultivated and in which, at the same time, the said chamber is furnished with a sensor. The chamber possesses an inlet and an outlet channel. Driven by a liquid pump, the culture medium flows through the perfusion chamber. In periodic, successive intervals, follow phases with perfusion and phases without perfusion, one after the other. The phases with perfusion serve for regeneration of the culture medium, the phases without perfusion aid the procedure for measurement, that is, the direct follow-up of the extra cellular acidification in the perfusion chamber.
However, it is disadvantageous that a high apparatus expenditure is present, since a liquid drive pump, valves for the control of the liquid flows as well as hose running and all are necessary.
A further disadvantage is that a certain predisposition exists for the formation of air bubbles in the perfusion chamber. These disadvantages can only be excluded at a comparatively high expense. Contributing to the expense, is the fact that equipment for partial degassing of the medium is necessary, which must be coupled with the cell cultures. As a whole, this increases the expense. Finally, a relatively higher labor involvement is required, in order to achieve an air bubble free and an airtight and watertight assembly of the system. This gives a particularly disadvantageous effect, when a multiplicity of parallel samples are to be tested, which is the rule in general practice.
FR-A-2 690 926 discloses a bioreactor, which possesses a container, in which solid particles can be brought into contact with a liquid. In the container is placed a piston, so that the volume of the reactor can be changed.
WO-A-90/04645 makes known a micro-through flow chamber in which cells for investigation as well as a sensor can be found. By means of an inlet and an outlet, the through-flow chamber is in communication with the outside environment.
EP-A-0 608 153 discloses a dosage apparatus with a reaction chamber. Within the reaction chamber a piston is inserted. Laterally, on the wall of the reaction chamber lines are connected, at various distances from the bottom of the reaction chamber, each of which is open or covered, according to the position of the piston.
These three above named documents concern themselves with apparatuses, which are comparatively expensive and complex in construction. An investigation of cells by means of the installation of the different, geometric environmental conditions for cell cultures is, on this account, not possible.